VOL. 40, No.


JUNE 1 964




Professor of Pathology, Coltollmbia Unjiversity ('ollee of lPhNsicins and Surgeons; Pathology Laboratories, Francis )elafieldfl ositmal, New Y ork


25ZDANCER is best conceived of as a disturbance in a com| munity of cells which, under normal circumstances, is


types in which a delicate physiological mechanism a~z5E5E~e552 termed homeostasis keeps order. For years I, as well as others, taught that the cancer cell is autonomous and unrestrained and that the nucleus of the cancer problem resides in this rebellious mutant cell. WVe were correct in supposing that most cancer cells were altered but were wrong in ignoring the existence of host factors to which many cancer cells are responsive, and we were wrong in failing to realize that alteration in the controlling forces also can lead to the formation and progressive growth of tumors. We did not recognize that the basic change toward malignancy can reside in the regulatory

[ticomposed of a specific number of cells of different cell

system." 2
This concept is founded on experimental evidence in animals and on observations in man. In man, events are often subject to several
n * The Aonnual .Scioim'lwveis Lecture' of the Ainetc-ic,-in-latitaL Mtei.dtl 'Medical Association, presentel at The New York Academy of Me(licine, Noveinher 9, 190(2. lhe work in the anithor's laboratory has been suppaioited ibs tile National (Cancer listitote of the National I nstitntes of Health, Bethesda, M\l1.

In animals. they often respond to the same stimulating and restraining forces. Deranging the system at various points can produce hyperfunction of either type of cell which. Today we conceive of a neoplastic cell as an altered cell which perhaps as often as not retains the basic features of its ancestors. on the other hand. is not especially concerned with a frontal attack to control a disease by trial and error. and its practical application. faced with the problem of what to do for his patients with breast cancer. This quantitative difference results in disorderly growth. trying to get answers on basic questions as he sees them. A few of these errant cells can be arrested by tilting the balance of the homeostatic forces toward restraint. he confronts the problem from a different perspective. For the clinician. a topic not yet fully explored. Thyroid hormone inhibits pituitary thyrotropes. may result in the formation of tumorous growth either of Bull. the clinician Beatson.' The three main cancers for which manipulation of the homeostatic mechanism has been successfully attempted are those of the mammary. He therefore introduced into the treatment of breast cancer the removal of the ovary which is a pacemaker of the growth and function of the mammary gland. Primum non nocere.3 This brilliant concept. The best known homeostatic system is that between the thyroid and the pituitary thyrotropes. Med. Y. N. FURTH j. The level of knowledge about mammary cancer that has been attained illustrates how progress is achieved by the cross-fertilization of the two avenues of approach. prostate. though usually to a lesser degree. and thyroid glands. Such cells look and function more or less like their predecessors.42 4 424 J. getting the patient well is the primary objective. . led to a host of major theoretical contributions on the role of hormones in the initiation and maintenance of many neoplasms. if the stimulation is sustained. In I896. The research man. proof can be sought two ways. FURTH interpretations and the possibilities of substantiating observations by experimental proof is limited. clinical and laboratory. Many cells can be retarded by this means but some are entirely unresponsive to physiological corrective measures. Acad. by inducing or aggravating a disease and by preventing or alleviating it. pituitary thyrotropes stimulate thyroid cells. conceived the idea that what stimulates the normal breast may also stimulate cancer.

PATHOGENESIS AND C'ON rROL OF BREAST CANCER 42 5 thyroid cells or of the pituitary thvrotropes. One leading mouse tumor virologist is a crusader for the idea that women should not nurse their babies because he believes that in wvomen.4 Although the feedback mechanism connecting the mammary gland with the pituitary is not known. in turn. Many tumor virologists believe that a virus plays a major role in the induction of mammary tumors in all species. Wlrhen it was found that the adrenal gradually compensates for the al)sence of ovarian hormones resulting from oophorectomy. June 1964 .(. No. 7 In the meantime. recognition that the pituitary controls both adrenal and gonadal functions led to the introduction of hypophysectomily. laboratory research imiadc several fundamental contributions. experimental evidence Vol. The discovery that rat tumors are highly hormone-responsive gave rise to the belief that "extinction" of mammary tumors is possible. it has been established that androgens are to some extent antagonistic to estrogens. In the following we shall sketch the basic process and mechanisms leading to the control of mammary tumors. Oophorectonly beyond doubt restrains many mammary tumors of man and experimental animals.2 A common disturbance in man is depression of the thyroid function byt goitrogens. a virus is the prime cause of breast cancer and that this virus is acqu ircd with the mother's milk. the nmammniotrope which can stimulate the maiiimary gland even in the absence of the ovaries. But only recently has it been solidly established that estrogens act mainly by stimulating a special pituitary cell. as in Mice. adrenalectomy for control of breast cancer of women was introduced.11 While this is a possibility. Large doses of estrogens inhibit the same mammary tumors which they can stimulate in small doses. they are not identical in biological behavior. The isolation of ovarian hormones soon led to the identification of estrogens as the usual ovarian stimulants. 40. 6.5 Finally.. Mlost mouse mammary tumors differ from rat mammary tumors in that they are highly autonomous and are linked to a virus 10 which appears to be specific to this species.This upsurge of optimism camiouLflaged the fact that procedures which conmpletelv cure rat imammllilaryr tumors fail to cure human mammary tumors. causing hypersecretion of thyrotropic hormone. produces thyroid tumors. which. It was found that though the various types of mammary tumors occurring in wd omen are similar to those il nlice and rats.

So far three classes of carcinogens are known: i) viruses. Figure i is a schematic presentation of similar events in experimental animals bearing niamiary tumors Bull. apparently virus-free mammary tumors of the rat have disclosed interesting phenomena. though less often than Cohnheim conceived.. HWhile it is simple to produce mainnmary tumors in mice and rats by these three types of carcinogens 1 2 (and to prevent or control many mammary tumors). Regression of human mammary tumors following oophorectonmy. of which one might be a virus. which implies irreversible alteration of cells. . In addition. . It may trigger ineoplastic transformation without carcinogenic insults. they can also influence the formation and progressive growth of many cancers. play a determining role in the formation of mammary tumors by the three classes of carcinogens named and in the growth of many of the induced tumors. Acad.42 42 6 H FRT J. Hereditary liability and hormones are more likely to be promoters than to be prime instigators. readily do so w\lhen the mammary gland is stimulated by the mlaniliotropic hornmoncs. of exploration. Y. Studies of both the hormone-independent viral mammary tumor of the mouse and the highly hormone-dependent. the mamnnotrope.13 Under appropriate physiologic conditions hormones arc specific regulators of the growth and functioning of cells. However. N. and 3) radiation. No mamnmarv tumor virus has been identified thus far in species other than the mouse. and pronmotion. Heredity is an ever-present modifier of host response. These studies are not immediately applicable to man but are beacons pointing to conceivable similarities in man which are worthy. which are incapable of producing mammary tumors alone. adrenalectomy and hypophysectonly has been amply illustrated in publications of numerous investigators. Work in our laboratories led to the conclusion that hormones of the pituitary cell.12 Small doses of carcinogens. The process of carcinogenesis has several comiponents. the mammary carcinogens of man are unknown. a process in which the initial cells are stimulated to proliferate. among w\vhichl are initiation. Experimental evidence supports observations in man indicating that cancer is not a single disease and that the same type of cancer can be induced by different agents. 2) certain chemicals. hereditary factors play a significant role in tumorigenesis. Med. UT is better interpreted as indicating that cancer has manv causes and that carcinogenesis can be triggered by various means.

and following tnitior regression iaiillmotropic hormones were administered by means of grafts of functional inammotropic cells.) and also shows proof that regression of miammiary tumor was caused iby elimination of maimmnotropes. Stalk section is not the same as hypophysectomy in that it does away wvith 1ypotlhalamic inhibitors but does not eliminate the secretion of nmammi-otropins. shows that this effect is attained by removal of mammotropes. (See Ref. 1. 6. The neoplastic change in cells results in the creation of new cells witlh different characteristics. the neoplastic alteration is not fixed Vol. 40. Estrogens given to hypophysectonlized animals failed to do so. Analysis of the beneficial effects of hypophxysectomy in the control of mammni-nary tullor in XwomIIenI as wvell as in the rat. iH MtH I _ / 1j _ _ _ - 20 40 60 80 100 DAYS 120 140 160 180 Fig. and c) autonomous. Replacement of the latter caused a rapid recurrence of the regressed mammary tumor. Theoretical considerations negate its clinical use. Accordingly. 4.' Furthermore. Results of a representative experiment in which various operative procedures wvere )erforlme(d on naimiiniary tNitmor-bearing rats.PATrHOGE[NESIS ANI) ('()NtTROL OF BREAST CANCER 42 7 S / / N ILL C. three types of cancer cells have been recognized: a) hormone-dependent. No. Cancer cells are unlike normal cells in that they fail to respond properly to the normal homeostatic regulators or do not recognize them at all. June 1964 . Figure 2 showvs that mammotropic hormones (i\ ItH) reverse the inhibition of mammary tumor growth in hypophysectomized rats. b) hormone-responsive.

10 ./ / 4. (-7%) 5 ( LBeginning of treatment 0 90 100 11d 0 I 130 140 150 Days . 2 The effects on mannnary tuniors of estra(liol 17.42 42 8 . Although the information obtained from sttudies of mamiliary tumIlors in one species is not immediately transferable to other species. the more aggressive variant gradually outgyrowing the less aggressive omec. N. Acad. 4. Rat mammarv tUmors arc of the first or second.1.1 In man. T MtT graft _ *1% HIM.t 30 (*337%) / 4/ E25 -/ E 2/ E~~~~ 211%) 2020 E~~~~~~~ Ea * 15/ .a ad(hmlinistered by gra fts of fun(ctional imninnuiotropic cells ( Mt'l) Note that MtTi and sniall doses of estrogeni stimnittlated. . nd iumainniiotropic hormiones Fio '-. FURTH UF 35 . ..) but is subject to further modificatiois. As to the precise events by -which carcin1ogcles and promoters exert inlflueCnce. (From Kim and others. o / -A=. 1--O ~~/ . Failure to identify -with certainty virus particles in electron Bull. Med. and hi r-e (loses of estrogen inhihited this tuiIor. the basic mechanlisms of formation andc growth of mammary tumors appear to be alike in the different species. mnuch is still to be learned in all species. Ref. . Y. nearly all mammarVy tumors that hiavc l)ecl studied are of the second or third type. and mouse miammary tumors arc of the third type. The niature of hiumani mammary carcinogens is not better understood than that of the mammary carcinogens of the rat.

The ease of induction of mammary tumors by chemicals is readily explained by their entrapment in the mammary gland. Since tumors vary in hormone responsiveness. 40. Isolated oophorectomy is inadequate. June 1964 .PATHOGENESIS AND) CONTROIL OF BREAST CANCFR 429 micrographs of either 11hum1an or rat mammary tumors is notewvorthy but not conclusive. It is desirable to deprive tumor hosts of all mammary glandstimulating factors as soon as possible after discovery of the tumor. Experimental studies indicate that neoplastic cells can not only acquire resistance to the inhibitors of the ancestral normal cells but can even become stimulated by them. 6." e. Short-term in -vitro or in7 vLlivo techniques are also conceivable.g. SUMMARY AND RECOMMENDATIONS How can recent experimental findings in regard to mammary tumors be utilized in the control of human breast cancer and how can laboratory research shed additional light on the genesis of mammary tumors? There are several possibilities: I. organ cultures are at present of greatest promise. notably with the use of tritiatecd thymidine uptake as an index of growth activity.' 2. it is desirable to devise methods to demonstrate the degree of responsiveness of a given tumor to given hormones. No. That the incidence of manmmary tumors in irradiated women is not significantly different from that in nonirradiated women is best documented by the recent Hiroshima statistics. This can be accomplished by either surgical ablation of the respective hormone-producing organ or by endocrine "ablation. The mammary gland is a secretory and excretory organ. notably by increasing the number of carcinogen-sensitive mnitotic stages. inhibition of mammary gland stimulators. The higher incidence of tumor in women who did not lactate may possibly be explained by supposing that in stagnating milk the carcinogens xvere trapped in the breast whereas the nursing mother excreted the carcinogens with the milk. The main promoters of human mammary tumor are those agents which stimulate the mammary gland and thereby increase the chance of "capture" or retention of the carcinogenic substances and enhance the sensitivity of the cells to carcinogenic modifications. Radiation can produce mnammary tumors in most rats but does so less readily in mice. To this end. Vol. Carcinogenic chemicals are excellent mamimnary carcinogens in the rat.

If a mammary tumor is fully autonomous. but it was found that hormones produced by this cell also have growthpromoting. 3. Ablative procedures performed in succession. Clarification of the relation between growth hormone and prolactin is desirable. alone and combined in various doses. removal of niammotropes Bull. adrenal corticoids and pituitary hormones. Quantitative serologic tests of the pituitary hormones hold promise of solving some of the problems discussed. Further studies are needed on the mode of action of various sex hormones. While the beneficial effect of adrenalectomy is well established. and hematological means constitute one of the most fascinating areas of endocrinological research. increase the hazard. 4.e. Acad. 7. Y. too. Med. The pituitary cell producing the hormones commonly called "prolactin" has been isolated. have some effect on the mammary gland. assaying their levels during evolution and growth of mammary tumors is desirable. 6. less hormone-responsive variants which were not present at the time of the first successive ablative therapy. as now practiced. because of the additional time allowed for the emergence of more autonomous. . FURI1-I H FURT for the fulcrum of the control of the mammary gland is the pituitary.430 43 0 .1. 5. Such research wvill lead to clarification of the pituitary mosaic and feedback function. theoretically optimal choice is either combined adreno-oophorectomy or hypophysectomy. and even some adrenotropic properties. e. as currently practiced. i. adrenalectomy following oophorectomy. the mechanism by which this is attained is not entirely clear. Corticoids. The former accomplishes about as much as com11plete 1vpoplhvsectomyNr if n10 functional accessory adrenal is present. Al\ost human mammary tunmors are somewhat hormone-responsive even though they are autonomous. J. Isolated oophorectomy is inadequate because the adrenal is likely to compensate by producing inammotrope-stimulating estrogens. endocrine-specific manipulations are of no help. Secondary hyperplasia of these cells is a menace. The labeling of these hormones will help to pinpoint the various cell types of the pituitary. chemical.g. 8. is not comparable to oophorectomy because the radiation-induced ovarian atrophy does not lead to destruction of all estrogen-producing cells. Isolation and analysis of the pituitary hormones by physical. If a mammary tumor is hormone-responsive. Ovarian sterilization by radiation. Since the best known direct stimulants of the mammary gland are the maminiotropic hormones. N.

In Endocrine Aspects of Breast Cancer.1. 6. 12:134-41. C. lpP 34-41. 1946-1947. Furth. Nat. J. C. 1896. 1954. Churchill. Hypophysectonmv in the mimanagement of metastatic carcinoma of the breast. 1941. 23:21-34. K. Influence of host factors on the growth of neoplastic cells. No. G. Ltd. REFERENCES 1. 2. J. and Bergenstal. In this endeavor.. Cancer Res. 0. 14: :327-39. Furth. Cancer Inst. Beatson. 40. Sary. and Yannopoulos. Currie. T.. E. 1962. D. J. 8. Vol. Furth.. Experimental study of tumor progression: Review. 12. 1952. with illustrative cases. J. and Yang. Clin. Kim. 1963. Conditional neoplasrus and subthreshold neoplastic states. 31 :23359. Hypop)h1ysectommmy in treatment of a(lvanced 9. J. Y. Vistas in the etiology and pathogenesis of tumors. B. Edinburgh. Amer. 27-85. 1956. C. This calls for intensification of the search for steroids which inhibit mammotropes. 1958. 0. and Kidd. Livingstone. Lancet 2:104-107 (July 11). J. June 1964 . study of the significance of cocarcinogenic action and related phenomuena. E.5. Bittner. G. RouIs. 1962. study of tar tumors of rabbits. Concept of conditioned and autonomlous neoplasms. Thus the clinical and laboratory advances bring new vistas in knowledge of mammary gland physiology and pathology and in prophylaxis and control of breast cancer. 13. R. L. and others. Observations on hormonal control of mnammary cancer. Estrogen and mamamotropes. . Fed. 7. 3. Huggins. Inhibition of human malmmary and prostatic cancers by adrenalectomy. Furth. Ciba Foundation Symposium on Leukemia Research. U. IHypophysectomy in treatment of disseminated breast cancer. 1:807-14. 4. Berenblumi.7:257-62 (July 27). Gross. P. Foulds. though it does not arrest their growth. On the treatment of inoperable cases of carcinoma of the manuna: Suggestions for a new method of treatment.: 394-403. Med. I. M. . A. B. 10. 42: 419-33. Proc. N. Cazcer Res. Cancer Res. ed. R. Mechanismi of carcinogenesis. and Pearson. & S. In women with high breast cancer hazard. J. Ann. cancer of the breast. Sury. 42?:22-4(i. 1963. 1941.. S. H. Induction and extinction of mammnary cancer. Possibility of preventing breast cancer in women. J. 1961. work with experimental hormoneresponsive mammotropic tumors may be helpful. S. 1947. 47:866-67. LuIft. Harvey Lect. & A. N. Huggins. pp. Med. J. . Is artificial feeding of infants justified? N. it may be possible to intensify their action by introducing strong radioactive or cytostatic agents into the hormone molecule without destruction of hormonal specificity. 1. 1954.1p). 6. Ray. Should niainnmotropes prove to be direct stimulants of mammary tumors through contact with the cells. 11. London. Ltd. H. 14.PATHO(CENESIS AND CONTROL OF BREAST CANCER 4 3 I inhibits.20: 865-73. Cancer Res. and Pearson. Ray. Causes and control of miammniary cancer in mice. 14.5. J. prophylactic hormonal depression of the pituitary mammotropes might be considered. I. Science 1X. 9. 73:365-90. L.

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